The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Diagnostic imaging techniques, such as magnetic resonance imaging (MRI), X-ray, nuclear radiopharmaceutical imaging, ultraviolet-visible-infrared light imaging, and ultrasound, have been used in medical diagnoses for many years. MRI and optical imaging methods are unique among imaging modalities in that they yield complex signals that are sensitive to chemical environment.
Magnetic Resonance Imaging (MRI) obtains images of the body in thin slices by measuring the characteristics of hydrogen nuclei of water (and nuclei with similar chemical shifts), modified by chemical environment across the slice. The signal intensity depends on the amount of water in a given place and on the magnetic relaxation times. It is this latter characteristic that can be manipulated with the use of contrast agents to change the signal intensity and the appearance of different tissues on the MR image.
Contrast agents are chemical substances introduced to the anatomical or functional region being imaged, to increase the differences between different tissues or between normal and abnormal tissue, by altering the relaxation times.
Achieving sufficient sensitivity is a significant problem for MRI in particular, where concentrations in the range of 10-1000 μM of the image enhancing moiety are required to produce an adequate signal. Accordingly, targeted agents may be utilised which deliver concentrations of the imaging agent to the target so that sufficient improvement in the signal is observed during the course of imaging. Even then however, the problem can be further complicated for targeted agents if the desired target is present at low concentrations. For example, in order to image biological receptor targets that are present at less than μM concentrations, great signal enhancement is required at the target site to prove sufficient image contrast.
The most commonly used contrast-enhancing agents are paramagnetic species such as metal ions. Gadolinium (Gd) is preferred because it has seven unpaired electrons that produced an especially short paramagnetic effect on adjacent water protons. Since paramagnetic metal ions useful for relaxivity enhancement are usually toxic, placing such ions in physiological compatible complexes reduces their toxicity without substantially reducing their effectiveness.
Presentation of a plurality of paramagnetic particles enhances the use of a contrast-enhancing agent. It also reduces the amount of contrast agent actually required compared to agents having macromolecules bearing fewer particles. For example, it is believed that a 50% reduction in T1 relaxation time of water protons in a target tissue is a requirement for an effective MRI contrast agent. Analysis of tumor enhancement for MRI using an antibody conjugated with 4 Gd atoms per antibody molecule found no tumor enhancement and predicted that a far greater ratio of imaging metal atoins per macromolecule would be required.
Conventional MRI contrast-enhancing agents have only one chelant per molecule. These agents are typically short-lived in the subject's body or other physiological environments. Thus, in many instances, large doses must be administered in order to achieve a desired degree of contrast enhancement. In other instances, maximal contrast enhancement cannot be achieved without administering a potentially fatal or otherwise physiologically intolerable dose to the subject.
There exists a need therefore, for new imaging agents which may advantageously provide multiple signalling or imaging entities and/or specifically target cell or tissue types.